Angewandte
Chemie
[
3]
[4]
ity and also catalyzes asymmetric cyanosilylation. Herein
we disclose another synthetically useful feature of diphenyl-
prolinol (1), the silyl ethers 2 of which were found to be
exceptionally effective in the asymmetric catalysis of the
ically, along with the enantioselectivity, when the hydroxy
group in 1 was exchanged for a siloxy group. That is, the
reaction was complete within 1 h at room temperature in the
presence of the diphenyl siloxy proline 2a, and the adduct was
afforded in good yield (82%) and with increased enantiose-
lectivity (99% ee; Table 1, entry 4). When the reaction was
performed at a lower temperature (08C), the adduct was
obtained in nearly optically pure form (99% ee), in good
yield, and also with high diastereoselectivity (syn/anti 94:6;
Table 1, entry 5). The catalyst loading can be reduced to
5 mol% without compromising the enantioselectivity, but the
reaction must then be carried out at room temperature, and a
longer reaction time is needed. Not only the TMS-substituted
compound 2a, but also the TES and TBS derivatives 2b and
2c are excellent catalysts; however, the reaction becomes
slower as the silyl substituent becomes bulkier. As excellent
results had been obtained with the model system, the
generality of the reaction was examined in detail, with the
results summarized in Table 2.
The reaction has broad applicability with respect to both
the Michael acceptor and the donor; the adducts were
obtained in nearly optically pure form (99% ee) and with
excellent syn diastereoselectivity in most of the cases
examined. Both aryl- and alkyl-substituted nitroalkenes are
excellent Michael acceptors: Not only phenyl, but also
electron-rich and electron-deficient aryl groups and hetero-
aromatic substituents can be present on the nitroalkene.
Alkyl-substituted nitroalkenes, such as 1-nitro-1-hexene and
2-cyclohexyl-1-nitroethene, are also excellent Michael accept-
ors (Table 2, entries 5 and 6). Not only propanal, but also
other linear aldehydes, such as n-butanal and n-pentanal
[
5]
Michael reaction of aldehydes and nitroalkenes.
The Michael reaction of a carbon nucleophile with a
[
6]
nitroalkene is one useful synthetic method for the prepara-
tion of nitroalkanes, which are versatile synthetic intermedi-
ates owing to the various possible transformations of the nitro
group into other useful functional groups. The need for
environmentally friendly and metal-free reactions has led
recently to great progress in the organocatalyst-mediated
Michael addition to nitroalkenes: Asymmetric Michael
reactions of malonates and b-ketoesters as nucleophiles are
promoted by a cinchona-alkaloid derivative and a bifunc-
tional thiourea catalyst. The reactions of ketones and
aldehydes as nucleophiles are catalyzed by proline, pyrro-
lidinyltetrazole, aminomethylpyrrolidine, and 2,2’-bipyr-
[
7]
[
8]
[
9]
[
10]
[11]
[
12]
rolidine.
excellent Michael reaction of ketones with a pyrrolidine
catalyst that includes pyridine as the conjugate base.
Kotsuki and co-workers have developed an
[
13]
Recently, Wang et al. reported a highly enantio- and diaster-
eoselective Michael reaction of aldehydes, although the
catalyst loading was high (20 mol%) and an alkyl-substituted
nitroalkene was a poor Michael acceptor (22% ee). The
development of more-effective asymmetric catalysts in terms
of both enantioselectivity and substrate scope is desirable.
The Michael reaction of propanal and nitrostyrene was
selected as a model [Eq. (1), Table 1]. The first catalyst
[
14]
(Table 2, entries 9 and 10), and branched aldehydes, such as
isovaleraldehyde (Table 2, entries 7 and 8), can be employed
successfully as the Michael donor, again to afford the adducts
in nearly optically pure form. In the reaction of (Z)-nitro-
[
15]
styrene with propanal, the same high levels of diastereo-
and enantioselectivity were observed as those found in the
reaction of the E isomer (Table 2, entries 1 and 11). In this
reaction, the rapid isomerization of (Z)-nitrostyrene to the
corresponding E isomer was observed by TLC. This method
also has its limitations, however: Isobutyraldehyde was found
to be a poor nucleophile; in its reaction with nitrostyrene the
product was afforded with only moderate enantioselectivity
(68% ee; Table 2, entry 12). The b,b’-disubstituted nitroolefin
(E)-2-methyl-2-phenyl-1-nitroethene was found to be a poor
Michael acceptor, with the desired adduct formed in low
yield.
Table 1: The effect of the catalyst in the Michael reaction of propanal and
nitrostyrene.
[
a]
[b]
[c]
Entry Catalyst (mol%) T [8C] t [h] Yield [%]
syn/anti
ee [%]
1
2
3
4
5
6
7
8
3 (20)
4 (20)
1 (20)
2a (10)
2a (10)
2a (5)
2b (10)
2c (10)
0
0
23
23
0
23
0
0
24
24
24
1
44
25
29
82
85
85
72
80
97:3
28
75
95
99
99
99
99
99
92:8
86:14
85:15
94:6
96:4
93:7
95:5
5
38
22
27
1
[a] Yield of isolated product. [b] Determined by H NMR spectroscopy
(
400 MHz). [c] The ee values were determined by HPLC analysis on a
A preliminary study showed that not only nitroalkenes,
but also a,b-unsaturated ketones can be employed as the
Michael acceptor: 3-Phenylpropanal reacted with methyl
vinyl ketone in the presence of 2a to afford the Michael
chiral phase (chiralcel OD-H).
[
16]
examined, proline (3), led to a low yield and low enantiose-
lectivity (Table 1, entry 1). Higher enantioselectivity
adduct
benzyl].
in 52% yield and with 97% ee [Eq. (2); Bn =
(
75% ee) was observed with the siloxyproline 4, but the
yield was poor (Table 1, entry 2). Although excellent enan-
tioselectivity (95% ee) was observed when diphenylprolinol
(1) was employed, the progress of the reaction was slow, and
the yield was unsatisfactory (29%) even after 24 h (Table 1,
entry 3). The reactivity of the catalyst was increased dramat-
Angew. Chem. Int. Ed. 2005, 44, 4212 –4215
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4213
Hayashi, Yujiro
